Drug-adapted cancer cell lines as preclinical models of acquired resistance

Abstract

Acquired resistance formation limits the efficacy of anti-cancer therapies. Acquired and intrinsic resistance differ conceptually. Acquired resistance is the consequence of directed evolution, whereas intrinsic resistance depends on the (stochastic) presence of pre-existing resistance mechanisms. Preclinical model systems are needed to study acquired drug resistance because they enable: (1) in depth functional studies; (2) the investigation of non-standard treatments for a certain disease condition (which is necessary to identify small groups of responders); and (3) the comparison of multiple therapies in the same system. Hence, they complement data derived from clinical trials and clinical specimens, including liquid biopsies. Many groups have successfully used drug-adapted cancer cell lines to identify and elucidate clinically relevant resistance mechanisms to targeted and cytotoxic anti-cancer drugs. Hence, we argue that drug-adapted cancer cell lines represent a preclinical model system in their own right that is complementary to other preclinical model systems and clinical data.

Keywords: Cancer; acquired drug resistance; cancer cell lines; cancer models; cancer therapy; drug adaptation.

Figure 1

Many cancer diseases respond initially well to therapy but cancer cells become eventually resistant to therapy. An improved understanding of the mechanisms and processes underlying resistance formation is necessary to identify biomarkers that guide the use of efficient next-line therapies for tumours that have do not respond to the available standard therapies anymore

Figure 2

Members of the ATP-binding cassette (ABC) transporter family, including ABCB1 and ABCC1 as prominent members, belong to the most important mediators of drug resistance in cancer. Various members of the ABC transporter family function as efflux pumps that remove (often a wide range of structurally different anti-cancer drugs) from cancer cells and interfere with the achievement of effective intracellular drug concentrations

Figure 3

Drug-adapted cancer cell lines enable the identification of candidate biomarkers that enable the early detection of resistance formation and, in combination with drug screens and functional genomics approaches, the selection of effective next-line therapies